Diabetic macular edema (DME) is a major cause of vision impairment and blindness in patients with diabetic retinopathy1–4 and has a multifactorial pathogenesis.5,6 Hyperglycemia is a contributing factor to the pathogenesis of DME, leading to retinal neuroinflammation, oxidative stress, and vascular dysfunction. Evidence suggests that low-grade, chronic intraretinal inflammation serves as an early contributor to edema and pathogenic vascularization.7 Therapeutic targets for DME typically work to control edema, which is determined by retinal thickness measurements (eg, central subfield thickness [CST]), and assessed using best-corrected visual acuity (BCVA), in order to determine the functional outcomes of treatment.8
The impact of DME and treatment on patients' daily lives and wellbeing may be as important as the structural/functional outcomes (ie, CST and BCVA). Patient-reported outcomes and quality of life (QOL) measures represent valuable tools for the measurement of visual function-related treatment outcomes and enable management strategies to be developed to mitigate the impact of DME on patients' lives. Vision-related QOL measures (eg, social functioning and mental health) may also affect areas including treatment adherence/satisfaction. The high risk of non-adherence to treatment and follow-up appointments, and consequent increased risk of a loss in visual acuity (VA) and suboptimal treatment outcomes, has been documented.9
The National Eye Institute Visual Functioning Questionnaire-25 (NEI-VFQ-25), a health-related questionnaire with 25 questions, quantifies the impact of vision on QOL.10,11 Previous studies have used the NEI-VFQ-25 to evaluate QOL outcomes following DME therapies.12 Results have shown intravitreal vascular endothelial growth factor (VEGF) inhibitors are associated with meaningful improvements in BCVA and NEI-VFQ-25 scores during a period of 1 year.13–15 Previous exploratory analysis of the FAME study (NCT00344968) looking at driving subscale scores, measured using NEI-VFQ-25, concluded that these improvements were related to the better control of edema rather than central visual function as assessed by BCVA.16
Based on this previous work by Grewal et al.,12 the current exploratory post-hoc analysis of the Fluocinolone Acetonide in Diabetic Macular Edema (FAME) dataset examined the relationship between the control of DME provided by the 0.2 µg/day fluocinolone acetonide (FAc; Iluvien, Alimera Sciences, Alpharetta, GA) implant, patient-reported QOL, and BCVA during the 3-year treatment period. In the U.S., the 0.2 µg/day FAc implant is indicated for the treatment of DME in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure. The implant provides continuous microdose delivery of FAc for 3 years; alternative therapies (eg, anti-VEGF) typically provide shorter-term control of edema requiring repeated injections every 4 to 8 weeks to treat DME.1 The FAME study demonstrated that treatment with the 0.2 µg/day FAc implant in patients with DME provides a long-term, stable, and significant reduction in edema, and an improvement in BCVA.17
The objective of this post-hoc analysis of patients from the FAME trial, who received the FAc implant for the treatment of DME according to its licensed use in the U.S., was to assess patient outcomes (NEI-VFQ-25 and BCVA) based on area under the curve (AUC)-CST/day quartiles at baseline. This was done to determine how the control of edema with the 0.2 µg/day FAc implant impacted QOL outcomes.
Patients and Methods
The FAME study (NCT00344968) comprised two parallel, phase 3, randomized, double-masked, multicenter trials that assessed the efficacy and safety of the FAc implant versus sham injection in patients with DME.18 The studies adhered to the guidelines of the Declaration of Helsinki; the protocol and consent form were approved by each institution's governing Institutional Review Board/Ethics Committee. In the FAME study, the eye with the worse DME was treated with the FAc implant; in cases where DME was similar between eyes, the physician decided. The primary outcome of the FAME study was the percentage of eyes with 15 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters change in BCVA and mean CST (µm), assessed using optical coherence tomography (OCT) imaging. In the FAME trial, patients were allowed to receive rescue therapies at the discretion of the investigator. Overall use of these off-protocol intravitreal treatments was very limited and occurred at a low percentage in the (15.2%) FAc implant group as compared to the sham control (33.0%) thus limiting their potential contribution to the greater benefit seen in the FAc implant treated group as compared with the sham-treated group.
Three hundred twenty-four patients who enrolled in the FAME study completed the NEI-VFQ-25 at baseline (prior to FAc implant) and Year 3, and are included within this retrospective, post-hoc analysis. The area under the CST over time curve/day (AUC-CST/day) was calculated using the trapezoidal method. AUC-CST/day was based on intent-to-treat patients who had a baseline and at least one post-baseline follow-up assessment. This population, which represents varying degrees of control of edema associated with FAc microdosing, was used to analyze NEI-VFQ-25 changes.
Patients who completed the questionnaire were divided into quartiles depending on their AUC-CST/day during the 3-year period: Quartile 1 (159.0 µm to 259.4 µm), Quartile 2 (>259.4 µm to 310.9 µm), Quartile 3 (>310.9 µm to 408.9 µm), and Quartile 4 (>408.9 µm to 1129.5 µm).
As patients in Quartiles 1 and 2 have a smaller AUC-CST/day and better edema control versus Quartiles 3 and 4, the change in NEI-VFQ-25 scores during the 3-year period might be anticipated to increase less versus patients in Quartiles 3 and 4, who have poor edema control.
Questions were grouped into subscales and answered using a graded scale. Higher scores are associated with better vision-related functioning and QOL outcomes.19 Subscales analyzed were General Vision, Near Activities, Distance Activities, Social Functioning, Mental Health, Peripheral Vision, Ocular Pain, Role Difficulties, General Health, Dependency, and Color Vision.
Changes in NEI-VFQ-25 scores (primary outcome) and BCVA (secondary outcome) were assessed for each AUC-CST/day quartile. Treated eyes (better or equal vision to the fellow/untreated eye) were used for the analysis of AUC-CST/day and QOL. Despite clinically meaningful changes in NEI-VFQ-25 scores being considered as the benchmark for confirmation of real change,20 no published threshold is available for a clinically meaningful change in NEI-VFQ-25 score in DME.13,19,21 To align with a threshold used in patients in Submacular Surgery Trials Research,21 a 4-point change in overall NEI-VFQ-25 score and a 5-point change in subscale score were applied to reflect the proportion of patients who demonstrated a clinically meaningful change in vision-related QOL.
Baseline demographics of patients (n = 324) in the FAME study who completed the NEI-VFQ-25 are reported in Table 1. Based on quartiles, baseline CST correlated with AUC-CST/day over the trial period.
Baseline Demographics of Patients From the FAME Study With NEI-VFQ-25 Data
Vision-Related QOL in Patients With Better Edema Control: Quartiles 1 and 2
Patients with the lowest AUC-CST/day (Quartiles 1 and 2) showed significant increases in overall NEIVFQ-25 score from baseline to Year 3 (+7.4 points [P < .001]; +5.9 points [P = .004], respectively) (Figure 1) and significant increases in General Vision (P = .002; P < .001), Near Activities (P < .001; P = .002), Distance Activities (P = .002; P = .036), Social Functioning (P = .029; P = .039), Mental Health (P < .001; P = .011), and Peripheral Vision (P = .006; P = .031) subscale scores (Figures 2A–2F).
Overall National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ-25) score for all patients from baseline to Year 3. *P < .05; **P < .001; clinically meaningful change in NEI-VFQ-25 score shown by dashed line.
(A) General Vision, (B) Near Activities, (C) Distance Activities, (D) Social Functioning, (E) Mental Health, and (F) Peripheral Vision subscale scores from baseline to Year 3. *P < .05; **P < .001; clinically meaningful change in National Eye Institute Visual Functioning Questionnaire 25 (NEI-VFQ-25) score shown with a dashed line.
In all quartiles, changes in Ocular Pain (Figure 3A) and Role Difficulties (Figure 3B) scores correlated with AUC-CST/day quartiles from baseline to Year 3. The changes in Ocular Pain subscale score were non-significant in all quartiles; the change observed in Role Difficulties was significant in Quartile 1 (P = .034).
(A) Ocular Pain and (B) Role Difficulties subscale scores from baseline to Year 3. *P < .05; clinically meaningful change in National Eye Institute Visual Functioning Questionnaire 25 (NEI-VFQ-25) score shown with a dashed line.
Changes in General Health, Dependency, and Color Vision subscale scores were non-significant and showed no correlation with AUC-CST/day quartiles from baseline to Year 3 (Figures 4A–C).
(A) General Health, (B) Dependency, and (C) Color Vision subscale scores from baseline to Year 3. *P < .05; clinically meaningful change in National Eye Institute Visual Functioning Questionnaire 25 (NEI-VFQ-25) score shown by dashed line.
Vision-Related QOL in Patients With Worse Edema Control: Quartiles 3 and 4
Patients with the highest AUC-CST/day (Quartiles 3 and 4) showed no significant change in over-all NEI-VFQ-25 score from baseline to Year 3 (Figure 1). Quartile 3 demonstrated a significant increase in General Vision subscale score from baseline to Year 3 (<I>P = .004) (Figure 2A); Quartile 4 demonstrated a significant decrease in Dependency subscale score (<I>P = .016) (Figure 4B).
Best-Corrected Visual Acuity
Associations between AUC-CST/day and BCVA were observed from baseline to Year 3 (Figure 5). Patients in Quartiles 1 and 2, with the lowest AUC-CST/day, showed a significant increase in BCVA following FAc implantation from baseline to Year 3. In Quartiles 1 and 2, BCVA increased significantly by 11.5 and 9.9 ETDRS letters, respectively (P < .001) at Year 3. There was a large variation in the change in BCVA over the 3-year period in Quartiles 3 and 4.
Change in best-corrected visual acuity (BCVA) from baseline to Year 3: All eyes. ETDRS = Early Treatment Diabetic Retinopathy Study.
In study eyes, phakic at baseline, that had undergone cataract surgery by Year 3, changes in BCVA mirrored changes in the overall population across all quartiles (Figure 6). Pseudophakic eyes at Year 3 in Quartiles 1, 2, and 3 demonstrated a significant increase in BCVA from baseline by 12.2 (P < .001), 10.5 (P < .001), and 5.1 (<I>P = .027) ETDRS letters at Year 3, respectively. In Quartile 4, the increase in BCVA was not significant (0.7 ETDRS letters).
Change in best-corrected visual acuity (BCVA) from baseline to Year 3: Phakic-to-pseudophakic subgroup. ETDRS = Early Treatment Diabetic Retinopathy Study.
These analyses highlight that the range of benefits of consistent and long-term edema control can extend beyond improvements in BCVA and CST to broader aspects of QOL. This exploratory analysis of the FAME study identified greater improvements in NEI-VFQ-25 scores and BCVA in patients with better edema control compared with patients with worse edema control during the 3-year period. These outcomes are exploratory, and future prospective studies are required to fully characterize the applicability of these findings. Results suggest the importance of a durable therapy approach on overall improvements in QOL measures based on the continuous control of edema.
Findings from this study have shown that consistent control of edema with the FAc implant was associated with the greatest improvements in NEI-VFQ-25 scores. The greatest increases in NEI-VFQ-25 overall and subscale scores were displayed in patients with the lowest AUC-CST/day; Quartiles 1 and 2 had a significantly greater improvement in overall NEIVFQ-25 score versus Quartiles 3 and 4. Significant improvements were observed in eight of 11 subscales for Quartile 1 and six of 11 subscales for Quartile 2. This suggests that better edema control, throughout the FAc implant treatment period, resulted in greater improvements in QOL outcomes across a broader range of vision-related functions compared with patients with less optimal edema control.
The most significantly improved QOL outcomes were General Vision, Near Activities, Distance Activities, Social Functioning, Mental Health, and Peripheral Vision subscales. A clinically meaningful increase in General Vision subscale score was observed in all quartiles. In Quartiles 1, 2, and 3, this increase was significant. Despite having a clinically meaningful increase in General Vision subscale score, Quartile 4 (worst edema control) demonstrated a reduction in all other subscale scores. The reduction in subscores associated with Distance Activities, Social Functioning, Peripheral Vision, Dependency, and Color Vision were clinically meaningful. For these patients with the worst edema control during the 3-year period, the decrease in overall NEI-VFQ-25 score appeared to be clinically meaningful. The lack of improvements in QOL outcomes in patients with worse edema control may be associated with their overall decline in BCVA over time; however, this remains unproven in this exploratory analysis. This analysis does highlight the broader benefit of sustained edema control on patients' lives beyond improvement and stabilization of central visual acuity. In this study, patients who had better DME control, when compared with patients who had worse DME control, experienced a real change in their perceived general, near, distance, and peripheral vision, social functioning, mental health, and ability to carry out day-to-day activities during the 3 years post-FAc implantation.
Perceived improvements in QOL factors may lead to patients having more confidence to drive and participate in social interaction.22,23 Patients are more likely to continue to work and maintain independence in performing day-to-day activities compared with patients with a perceived poor visual function.24
The changes in Social Functioning and Mental Health subscale scores may be particularly relevant, as these subscales capture factors that may affect adherence/satisfaction with treatment. The frequency of feeling frustrated, irritable, embarrassed, or having a lack of control resulting from lack of or decreasing vision may impact a patient's treatment satisfaction. One study in patients with DME being treated with anti-VEGF reported non-adherence in 44% of patients after 1 year (median duration of treatment gaps: 88.0 days) and was associated with visual acuity (VA) loss and inferior clinical outcomes.9 There is potential for an increased adherence and decreased treatment burden with long-term FAc implantation compared with other treatment options available to patients with DME.
AUC-CST/day correlates with the amount of edema at baseline and represents a measure of control of DME over time. In this study, AUC-CST/day was assessed during a 3-year period using data collected during a phase 3 registration program. Patients with the least edema at baseline had the lowest AUC-CST/day, reflecting better control of DME during the trial, when compared with patients with greater baseline edema. This study also found that patients with less overall baseline edema and with better longitudinal control during the study demonstrated the greatest improvement in BCVA during the 3-year period compared with patients with worse baseline edema, who were more likely to experience a reduction in VA over time. This correlation was noted in both the phakic and pseudophakic subgroups, suggesting that an improvement in BCVA is not entirely dependent on lens status.
FAME A and B were randomized, controlled trials designed to evaluate the safety and efficacy of the FAc implant for treating diabetic macular edema in a large patient population without limits of disease duration. Thus, analysis results are focused on the full study population from the FAME study. This approach reflective of the U.S. label for the FAc implant. Additionally, the full study population provides a more complete dataset for exploratory analysis and interpretation. The NEIVFQ-25 was prospectively incorporated into a large phase 3 study to assess the QOL of patients who have received the FAc implant through 3 years. The data were analyzed post hoc in this study. The AUC method is relevant for sustained release treatments and long-term studies, especially considering the impact of short-term fluctuations.25 The AUC CST/day provides an average of the CST during the entire trial period, which is a more comprehensive clinical indicator of retinal thickness over time compared with single timepoint changes of macular retinal thickness.25,26
There are a number of limitations that need to be highlighted. Patient-reported outcome measures have limitations as they are dependent on patient self-reporting ability, which is subjective and may be impacted by treatment bias, memory, and human error. Patients included in our analyses refer only to the patients treated with the FAc implant in the full population of the FAME trial. Hence, it is not a comparative analysis versus sham treatment and does not assess outcomes in the pre-defined subgroup of chronic DME patients. Furthermore, this analysis is based on the outcomes of a randomized controlled trial, which may not be representative of patients with DME in a real-world setting.18 Additionally, patients did receive supplemental therapies in both sham and treatment groups, per the discretion of the investigator, that may have contributed to anatomic/functional outcomes. However, with these treatments being much more common in the sham group, their introduction would not contribute to the greater benefit observed in the FAc implant treated groups.
This post-hoc analysis found that patients with less severe edema at baseline may experience greater treatment benefit related to overall edema control, and that significant improvements in patient-reported QOL outcomes can be achieved with the FAc implant. Additional prospective studies are warranted to better understand broader visual function outcomes beyond BCVA among patients with DME.
- Das A, McGuire PG, Rangasamy S. Diabetic macular edema: pathophysiology and novel therapeutic targets. Ophthalmology. 2015;122(7):1375–1394. doi:10.1016/j.ophtha.2015.03.024 [CrossRef] PMID:25935789
- Romero-Aroca P, Baget-Bernaldiz M, Pareja-Rios A, Lopez-Galvez M, Navarro-Gil R, Verges R. Diabetic macular edema pathophysiology: vasogenic versus inflammatory. J Diabetes Res. 2016;2016:2156273 doi:10.1155/2016/2156273 [CrossRef] PMID:27761468
- Bahrami B, Hong T, Gilles MC, Chang A. Anti-VEGF therapy for diabetic eye diseases. Asia Pac J Ophthalmol (Phila). 2017;6(6):535–545. doi:10.22608/APO.2017350 [CrossRef] PMID:29076303
- Takamura Y, Ohkoshi K, Murata T. New strategies for treatment of diabetic macular edema. J Ophthalmol. 2018;2018:4292154 doi:10.1155/2018/4292154 [CrossRef] PMID:30210868
- Romero-Aroca P. Targeting the pathophysiology of diabetic macular edema. Diabetes Care. 2010;33(11):2484–2485. doi:10.2337/dc10-1580 [CrossRef] PMID:20980428
- Chakravarthy U, Yang Y, Lotery A, et al. Clinical evidence of the multi-factorial nature of diabetic macular edema. Retina. 2018;38(2):343–351. doi:10.1097/IAE.0000000000001555 [CrossRef] PMID:28257378
- Rübsam A, Parikh S, Fort PE. Role of inflammation in diabetic retinopathy. Int J Mol Sci. 2018;19(4):E942 doi:10.3390/ijms19040942 [CrossRef] PMID:29565290
- Eaton A, Koh SS, Jimenez J, Riemann CD. The USER study: a chart review of patients receiving a 0.2 µg/day fluocinolone acetonide implant for diabetic macular edema. Ophthalmol Ther. 2019;8(1):51–62. doi:10.1007/s40123-018-0155-5 [CrossRef] PMID:30560505
- Ehlken C, Helms M, Böhringer D, Agostini HT, Stahl A. Association of treatment adherence with real-life VA outcomes in AMD, DME, and BRVO patients. Clin Ophthalmol. 2017;12:13–20. doi:10.2147/OPTH.S151611 [CrossRef] PMID:29339917
- National Eye Institute. National Eye Institute Visual Functioning Questionnaire - 25 (VFQ-25) version 2000. https://nei.nih.gov/sites/default/files/nei-pdfs/vfq_sa.pdf. Published January 2000. Accessed February 8, 2019.
- Mangione CM, Lee PP, Gutierrez PR, Spritzer K, Berry S, Hays RDNational Eye Institute Visual Function Questionnaire Field Test Investigators. Development of the 25-item National Eye Institute Visual Function Questionnaire. Arch Ophthalmol. 2001;119(7):1050–1058. doi:10.1001/archopht.119.7.1050 [CrossRef] PMID:11448327
- Ramu J, Chatziralli I, Yang Y, et al. Health-related quality of life, visual function and treatment satisfaction following intravitreal dexamethasone implant for diabetic macular edema. Patient Prefer Adherence. 2017;11:579–586. doi:10.2147/PPA.S132859 [CrossRef] PMID:28360511
- Mitchell P, Bressler N, Tolley K, et al. RESTORE Study Group. Patient-reported visual function outcomes improve after ranibizumab treatment in patients with vision impairment due to diabetic macular edema: randomized clinical trial. JAMA Ophthalmol. 2013;131(10):1339–1347. doi:10.1001/jamaophthalmol.2013.4592 [CrossRef] PMID:23974915
- Granström T, Forsman H, Lindholm Olinder A, et al. Patient-reported outcomes and visual acuity after 12months of anti-VEGF-treatment for sight-threatening diabetic macular edema in a real world setting. Diabetes Res Clin Pract. 2016;121:157–165. doi:10.1016/j.diabres.2016.09.015 [CrossRef] PMID:27718374
- Garweg JG, Stefanickova J, Hoyng C, et al. AQUA Investigators. Vision-related quality of life in patients with diabetic macular edema treated with intravitreal aflibercept: the AQUA study. Ophthalmol Retina. 2019;3(7):567–575. doi:10.1016/j.oret.2019.03.012 [CrossRef] PMID:31080168
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- Campochiaro PA, Brown DM, Pearson A, et al. FAME Study Group. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology. 2012;119(10):2125–2132. doi:10.1016/j.ophtha.2012.04.030 [CrossRef] PMID:22727177
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- Submacular Surgery Trials Research Group. Evaluation of minimum clinically meaningful changes in scores on the National Eye Institute Visual Function Questionnaire (NEI-VFQ) SST report number 19. Ophthalmic Epidemiol. 2007;14(4):205–215. doi:10.1080/09286580701502970 [CrossRef] PMID:17896299
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- Singer MA, Miller DM, Gross JG, et al. Visual acuity outcomes in diabetic macular edema with fluocinolone acetonide 0.2 µg/day versus ranibizumab plus deferred laser (DRCR protocol I). Ophthalmic Surg Lasers Imaging Retina. 2018;49(9):698–706. doi:10.3928/23258160-20180831-08 [CrossRef] PMID:30222805
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Baseline Demographics of Patients From the FAME Study With NEI-VFQ-25 Data
|FAME Population With NEI-VFQ-25 Data|
|Demographic or Characteristic||Quartile 1 (n = 81)||Quartile 2 (n = 81)||Quartile 3 (n = 81)||Quartile 4 (n = 81)|
|Age (Mean ± SD, Years)||62.9±8.6||63.1±9.5||64.4±9.4||62.2±9.9|
|HbA1c (Mean ± SD, %)||7.5 ± 1.2||7.9 ± 1.6||7.9 ± 2.0||7.9 ± 1.6|
|Lens Status (Pseudophakic / Phakic, %)||45.7 / 54.3||37.0 / 63.0||33.3 / 66.7||27.2 / 72.8|
|Visual Acuity (Mean ± SD, ETDRS letters)||54.6 ± 13.0||55.3 ± 11.7||54.2 ± 11.0||49.1 ± 13.7|
|Central Subfield Thickness (Mean ± SD, µm)||402.6 ± 132.4||438.5 ± 142.1||447.9 ± 105.1||567.8 ± 136.6|